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Correlated Electrostatic Mutations Provide a Reservoir of Stability in HIV Protease

Omar Haq, Michael Andrec, Alexandre V. Morozov, Ronald M. Levy, Michael Gilson
2012 PLoS Computational Biology  
HIV protease, an aspartyl protease crucial to the life cycle of HIV, is the target of many drug development programs.  ...  Using a coarse-grained biophysical energy model together with statistical inference methods, we observe that accessory mutations of charged residues increase protein stability, playing a key role in compensating  ...  Acknowledgments We thank Emilio Gallicchio for many discussions and assistance with implementation of the coarse-grained Generalized Born electrostatic model. Author Contributions  ... 
doi:10.1371/journal.pcbi.1002675 pmid:22969420 pmcid:PMC3435258 fatcat:yki2eeqgdbb2vknunji5pdlk7u

Molecular Basis for Reduced Cleavage Activity and Drug Resistance in D30N HIV-1 protease [article]

Subhash C Bihani, Madhusoodan V Hosur
2021 bioRxiv   pre-print
AbstractNelfinavir is one of the FDA approved HIV-1 protease inhibitors and is a part of HAART therapy for the treatment of HIV-AIDS.  ...  Here, we have determined structures of D30N HIV-1 protease in unliganded form and in complex with the drug nelfinavir.  ...  Acknowledgement We thank late Dr Jean -luc Ferrer, FIP beamline, ESRF, for help in data collection and processing.  ... 
doi:10.1101/2021.02.28.433284 fatcat:qqanmvtaxbf2xbivjzvjyz7dce

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

Holly Heaslet, Ying-Chuan Lin, Karen Tam, Bruce E Torbett, John H Elder, C David Stout
2007 Retrovirology  
We have obtained the 1.7 A crystal structure of FIV protease (PR) in which 12 critical residues around the active site have been substituted with the structurally equivalent residues of HIV PR (12X FIV  ...  However, the flap regions of the 12X FIV PR more closely resemble those of HIV PR, having gained several stabilizing intra-flap interactions not present in wild type FIV PR.  ...  Mutations that increase stability in the flap allow a degree of cleavage of HIV substrates by FIV, but levels do not approach that obtained by HIV PR [17] .  ... 
doi:10.1186/1742-4690-4-1 pmid:17212810 pmcid:PMC1781954 fatcat:6zuizgjuxffmfmte3k47p7hyge

Structural basis for drug and substrate specificity exhibited by FIV encoding a chimeric FIV/HIV protease

Ying-Chuan Lin, Alexander L. Perryman, Arthur J. Olson, Bruce E. Torbett, John H. Elder, C. David Stout
2011 Acta Crystallographica Section D: Biological Crystallography  
PDB References: 6s-98S FIV protease with darunavir bound, 3ogp; with lopinavir bound, 3ogq.  ...  structure of wild-type HIV protease (Tie et al., 2004) . 3kfn is a complex of wild-type HIV protease with TL-3 and allosteric fragment 4D9 (Perryman et al., 2010) . 1b11 is a TL-3bound crystal structure  ...  Replacement of residues in FIV PR with homologous residues from HIV PR to create chimeric enzymes provides a system in which inhibitor specificity and pathways of drug-resistance development can be probed  ... 
doi:10.1107/s0907444911011681 pmid:21636894 pmcid:PMC3107052 fatcat:zziq3bzmjfhi3hvli5zv3w77ze

Molecular Analysis of the HIV-1 Resistance Development: Enzymatic Activities, Crystal Structures, and Thermodynamics of Nelfinavir-resistant HIV Protease Mutants

Milan Kožíšek, Jenelle Bray, Pavlína Řezáčová, Klára Šašková, Jiří Brynda, Jana Pokorná, Fabrizio Mammano, Lubomír Rulíšek, Jan Konvalinka
2007 Journal of Molecular Biology  
The combination of the D30N and L90M mutations significantly increases the enzyme vitality in the presence of nelfinavir, without a dramatic decrease in the catalytic efficiency of the recombinant enzyme  ...  Vitality values obtained for recombinant mutant proteases and selected PR inhibitors confirm the crucial role of mutations in positions 30 and 90 for nelfinavir resistance.  ...  Acknowledgements This work was supported by grant NR/8571-3 from the Ministry of Health Care of the Czech Republic and by a grant from the Ministry of Education (MSMT) of the Czech Republic within programs  ... 
doi:10.1016/j.jmb.2007.09.083 pmid:17977555 fatcat:g537eq4v3bchdc6v5r6vqioeoe

Structural mechanism for HIV-1 TAR loop recognition by Tat and the super elongation complex

Ursula Schulze-Gahmen, James H. Hurley
2018 Proceedings of the National Academy of Sciences of the United States of America  
Promoter-proximal pausing by RNA polymerase II (Pol II) is a key regulatory step in human immunodeficiency virus-1 (HIV-1) transcription and thus in the reversal of HIV latency.  ...  Here, the crystal structure of the TAR loop in complex with Tat and the SEC core was determined at a 3.5-Å resolution. The bound TAR loop is stabilized by cross-loop hydrogen bonds.  ...  Different approaches to a cure for HIV-1 infection include elimination of all viral reservoirs following reactivation of the latent provirus (referred to as shock and kill), immune control without reservoir  ... 
doi:10.1073/pnas.1806438115 pmid:30514815 pmcid:PMC6305006 fatcat:pecarj7cyvdwha35nqooiszbvm

Electrostatically constrained α-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide

Hiroki Nishikawa, Shota Nakamura, Eiichi Kodama, Saori Ito, Keiko Kajiwara, Kazuki Izumi, Yasuko Sakagami, Shinya Oishi, Tadayasu Ohkubo, Yuji Kobayashi, Akira Otaka, Nobutaka Fujii (+1 others)
2009 International Journal of Biochemistry and Cell Biology  
We found a strong correlation between the anti-HIV-1 activities of these peptides and the thermostabilities of the 6-helix bundles that are formed with these peptides.  ...  We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino terminal heptad repeat of HIV-1.  ...  Acknowledgements This work was supported in part by grants for the Promotion of AIDS Research from the  ... 
doi:10.1016/j.biocel.2008.08.039 pmid:18834950 fatcat:pvfrn7zy5nbdpe2dok2jgqgpmq

Watching proteins in motion

Mary Munson, Daniel N Bolon
2009 Genome Biology  
A report of the 23rd Protein Symposium 'Proteins in Motion',  ...  Madhavi Kolli (University of Massachusetts Medical School, Worcester, USA) provided evidence that in patients treated with HIV protease inhibitors, mutations in the protease and its substrates coevolve  ...  This reservoir of stability is thought to serve as a capacitor for functional evolution of these proteins by maintaining structure in the face of destabilizing mutations that increase the potential for  ... 
doi:10.1186/gb-2009-10-10-316 pmid:19863776 pmcid:PMC2784317 fatcat:2422i23gt5gjtixvninogskvby

Potts Hamiltonian models of protein co-variation, free energy landscapes, and evolutionary fitness

Ronald M Levy, Allan Haldane, William F Flynn
2017 Current Opinion in Structural Biology  
Potts Hamiltonian models of protein sequence co-variation are statistical models constructed from the pair correlations observed in a multiple sequence alignment (MSA) of a protein family.  ...  These models are powerful because they capture higher order correlations induced by mutations evolving under constraints and help quantify the connections between protein sequence, structure, and function  ...  Acknowledgement This work was supported by the National Institutes of Health P50 GM103368 and R01 GM30580.  ... 
doi:10.1016/ pmid:27870991 pmcid:PMC5869684 fatcat:iunvrurryzbuvjugfw3uof6eg4

HIV-1 anchor inhibitors and membrane fusion inhibitors target distinct but overlapping steps in virus entry

Dirk Eggink, Ilja Bontjer, Steven W. de Taeye, Johannes P.M. Langedijk, Ben Berkhout, Rogier W. Sanders
2019 Journal of Biological Chemistry  
Although we found a strong correlation between Env stability and resistance to HR2-based fusion inhibitors, such correlation was not observed for Env stability and VIR165 resistance.  ...  In contrast, resistance mutations in the HR1-binding site for the fusion inhibitors did not cause cross-resistance to VIR165.  ...  Overall, there was a very strong correlation between Env stability and resistance to T20 (Fig. 3D ) and a moderate correlation with resistance to T2635 (Fig. 3E) , supporting the link between Env stability  ... 
doi:10.1074/jbc.ra119.007360 pmid:30696772 pmcid:PMC6463712 fatcat:65si2pei2reohauln47r2koihy

Comparison of a retroviral protease in monomeric and dimeric states

Stanislaw Wosicki, Miroslaw Gilski, Helena Zabranska, Iva Pichova, Mariusz Jaskolski
2019 Acta Crystallographica Section D: Structural Biology  
Such a water molecule is completely unique not only in retropepsins but also in aspartic proteases in general. The C7A and C106A mutations do not influence the conformation of the protein.  ...  Retroviral proteases (RPs) are of high interest owing to their crucial role in the maturation process of retroviral particles.  ...  Funding information This work was supported by a grant (RVO 61388963) from the ASCR to IP.  ... 
doi:10.1107/s2059798319011355 pmid:31588922 fatcat:ygohm6cazrgrflgl5jaqdufx54

Implications for Viral Capsid Assembly from Crystal Structures of HIV-1 Gag1-278and CAN133-278†,‡

Brian N. Kelly, Bruce R. Howard, Hui Wang, Howard Robinson, Wesley I. Sundquist, Christopher P. Hill
2006 Biochemistry  
) in the mature HIV-1 particle, and makes an important interaction with the cellular protein cyclophilin A (CypA).  ...  Gag, the major structural protein of retroviruses such as HIV-1, comprises a series of domains connected by flexible linkers.  ...  We believe that this mutant provides a good model for the wild-type protein for three reasons. (1) It occurs in the middle of an exposed and inherently flexible 18-residue loop. (2) A related mutation  ... 
doi:10.1021/bi060927x pmid:16981686 fatcat:msvp3d3ugzh6feg5begvpe5elm

Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: Insights into mechanisms of general viral fusion and inhibitor design

Halil Aydin, Dina Al-Khooly, Jeffrey E. Lee
2014 Protein Science  
In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed  ...  A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization.  ...  Karen Siu for critical reading of the manuscript.  ... 
doi:10.1002/pro.2442 pmid:24519901 pmcid:PMC4005712 fatcat:ir42jkvtfzb47aqmskmzy4h6yi

Human Leukocyte Antigen (HLA) Class I Down-Regulation by Human Immunodeficiency Virus Type 1 Negative Factor (HIV-1 Nef): What Might We Learn From Natural Sequence Variants?

Philip Mwimanzi, Tristan J. Markle, Takamasa Ueno, Mark A. Brockman
2012 Viruses  
HIV-1 causes a chronic infection in humans that is characterized by high plasma viremia, progressive loss of CD4+ T lymphocytes, and severe immunodeficiency resulting in opportunistic disease and AIDS.  ...  We argue that efforts to fully understand the critical role of Nef for HIV-1 pathogenesis will require greater analysis of patient-derived sequences to elucidate subtle differences in immune evasion activity  ...  MAB holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity.  ... 
doi:10.3390/v4091711 pmid:23170180 pmcid:PMC3499827 fatcat:jxi7z6ffdzgmjg3fixsivzuz6q

Design of Mutation-resistant HIV Protease Inhibitors with the Substrate Envelope Hypothesis

Sripriya Chellappan, G. S. Kiran Kumar Reddy, Akbar Ali, Madhavi N. L. Nalam, Saima Ghafoor Anjum, Hong Cao, Visvaldas Kairys, Miguel X. Fernandes, Michael D. Altman, Bruce Tidor, Tariq M. Rana, Celia A. Schiffer (+1 others)
2007 Chemical Biology and Drug Design  
There is a clinical need for HIV protease inhibitors that can evade resistance mutations.  ...  The value of HIV protease (HIVP) as a drug-target is powerfully validated by the fall in morbidity and mortality of HIV-positive individuals when the protease inhibitors were introduced to clinical practice  ...  Acknowledgments We thank Ellen A. Nalivaika for providing protease specimens. Some protease inhibitors were obtained through the AIDS Research and Reference Reagent Program, NIAID, NIH.  ... 
doi:10.1111/j.1747-0285.2007.00514.x pmid:17539822 fatcat:gpf3sdaglbegpfvrjlqsxuu42a
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